18-substituted steroids and process for their manufacture



United States Patent This is a continuation in part of our copending application Serial No. 74,486,'filed December 8, 1960, now abandoned.

The present invention provides a process for the manufacture of iii-substituted steroids of the pregnane series and more especially of saturated and unsaturated 18-iodo-, l8-hydroxy, 18-oxo-pregnane compounds and pregnanelS-acids which contain in 20- position a free or functionally converted hydroxyl or 0x0 group. The 18-oxygenated steroids of the pregnane series are known to form a very important group of substances due to their biological interest. Thus the new potent genuine mineralcorticoid aldosterone is an l8-oxo-pregnane compound. Actions similar to aldosterone and its derivatives are displayed by related compounds with an 18-oxygenated function, e.g., the 18-hydroxy-corticosterone, 21-desoxy-aldosterone and their derivatives. The Iii-oxygenated pregnane compounds are also of great industrial importance as valuable starting materials and intermediates for the manufacture of the physiologically active compounds. The process of the present invention affords a method by which an oxyg'enated function is introduced directly into the l3-methyl groupof l8-unsubstituted steroids via an intermediate 18- iodated product.

It is known that it is possible to treat ZO-hydroxy-pregnane compounds with lead tetraacetate so as to bring about direct, selective substitution of the angular, not activated methyl group at carbon atom 13 of the intact steroid skeleton to yield 18:20-oxido-pregnane compounds. According to the present invention there are obtained l8-iodo, 18-hydroxy and 18-oXo-derivatives of 18:20- oxido-pregnane compounds. The 18-hydroxy-18,20-oxido-pregnanes and the 18-oxo- 18,20-oxido-pregnanes can also be looked upon as the cyclosemiacetals of l8-oxo- ZO-hydroxy-pregnane compounds and the lactones of 20- hydroxy-pregnane-18 acids. According to the reactions of the present invention there can also be obtained 18- iodo-20-hydroxyor 20-oxo-pregnane compounds, the aforementioned 18-unsubstituted 18,20-oxido compounds obtainable from ZO-hydroxy-iii-unsubstituted pregnane compounds by the action of lead tetraacylate and also l8-hydroxy-20-oxo pregnane compounds.

The essential step in the process of the invention consists in treating an Iii-unsubstituted ZO-hydroxy compound of the pregnane series with substances forming monovalent positive iodine, under such conditions as will bring about homolytic cleavage of any 20 hypoiodite formed. The first product which can be detected in such treatment is an 1S-halogen-ZO-hydroxy-pregnane. It can be isolated when the process of the invention is conducted in a suitable manner, for instance when the treatment with V the substance forming positive iodine is discontinued while unchanged starting material can still be detected in the reaction mixture, When the iodine-forming compounds are then allowed to react further, there are obtained 18-iodo-18:20-oxido pregnane compounds which are easy to hydrolyze to form 18-hydroxy-18:20-oxido- 2 compounds. The l8-iodo as 'well as the l8-hydroxy- 18:20-oxido compounds are also easy to oxidize, for example with compounds of hexavalent chromium, to form 18:20-lactones of ZO-hydroxy-pregnane-18-acids.

The 18-iodo-20-hydroxy-pregnane compounds can also be oxidized to form the l8-iodo-20-oxo compounds, or they may be hydrolyzed to form 18,20-oxido compounds unsubstituted in 18-position. In the 18-iodo-20-oxocompounds the 18-iodine atom can be exchanged for hydroxy and there are thus obtained the l8-hydroxy-20- oxo pregnane compounds which are mostly present in the tautomeric ZO-hydroxy-form.

The reactions occurring in the process of the present invention are reproduced in the following scheme of partial formulae: 9

on on ICH on l l l A B C OH HO CH to l 0 on, air

a on i The ZO-hydroxy-compounds used as starting materials are reacted according to the invention with substances forming monovalent positive iodine. Such compounds are, for example N-iodo-carboxylic acid amides and imides, for example iodosuccinimide or cyanogen iodide. The use of hypoiodous acid and its derivatives, for example ialkylhypoiodites such as tertiary butyl hypoiodite is particularly advantageous. Alkyl-hypoiodites may be prepared, for example from heavy metal oxides, such as mercuric oxide, silver oxide, lead oxide and the like, with iodine and alcohols. Especially suitable are acylhypoiodites which may be advantageously obtained from heavy metal acylates, for example acetates, propionates, trifluoroacetates, benzoates of the metals of the first and second sub-groups of the Periodic Table, for example from silver and mercuric acylates with iodine. Especially suitable is. the use of iacylates of tetravalent lead for example dialkyllead diacylates; preferred is, however, the use of lead tetraaeylates, such as lead tetraacetate, lead tetrapropionate, lead tetrachloracetate or the like. Monovalent, positive iodine is also contained in the compounds of iodine with other halogens, i.e., iodine chloride or iodine bromide. It is often an advantage to prepare the iodoreagent used, particularly the acylhypoiodites in the manner described above directly in the reaction solution itself.

The process can be carried out, for example, thus: The star-ting material is dissolved or suspended in a solvent that is inert towards the oxidant, for example in a hydrocarbon, whereupon iodine and lead tetra-acetate, mercuric acetate or silver acetate, are added, and the reaction mixture is then stirred with heating under atmospheric or super-atmospheric pressure. Particularly suitable solvents are saturated cyclic hydrocarbons, such as cyclohexane, methylcyclohexane or dimethylcyclohexane; aromatic hydrocarbons, such as benzene, or halogenated hydrocarbons, such as carbon tetrachloride, hexachloro butadiene, or mixtures of two or more of said solvents. In order to neutralize acid present or formed there may be added a weak base, for example, calcium, strontium or lead carbonate.

Non-polar solvents favor homolytic cleavage of the 20- hypoiodites as compared with heterolytic cleavage which would lead to 20-ketones. When hypoiodous acid or its derivatives, particularly acylhypoiodites, are used as reagents, they are preferably used in great excess, since these too undergo homolytic cleavage intocarbon dioxide and alkyl halide. From the acetylhypoiodite formed in the reaction of lead tetraacetate with iodine there is easily formed, for example methyl iodide and carbon dioxide.

For the reaction according to the present invention it is of advantage to work at a raised temperature, for example between 50 and 150 C. The reaction is also accelerated by irradiating the reaction solution with visible and/or ultraviolet light. It is often of advantage to add excess iodine to the irradiated reaction solution.

The speed of the conversion of a 20-hydroxy compound (A) into an 18-iodo-20-hydroxy compound B does not seem to dififer much from that of the conversion of B into the 18-iodo-18,20-ether C. However, as long as type A starting material can be detected in the reaction miture, iodo hydrin B can be isolated therefrom, while on prolonged reaction first A, then B, disappear. The best reaction period largely depends on the reagents used. In the case of lead tetraacylates and iodine with irradiation, it lasts but a few minutes, but is about 2 to 12 hours in the case of mercury acetate or silver acetate and iodine. At a suitable moment, the reaction can be interrupted by destroying the excess oxidizing agent, for example, by extraction by agitating the reaction solution with a reducing agent, e.g., a solution of sodium sulfite or sodium thiosulfate.

Alternatively, the reaction period can be shortened by reducing the quantity of the active oxidant, so that conversion of the entire quantity of A into C is no longer possible; the reaction mixture must then contain compound B. Accordingly, it is possible to react, for example, an Iii-unsubstituted ZO-hydroxy compound of the pregnane series with an oxidizing lead acylate in the presence of less then one molecular equivalent of iodine (calculated on the ZO-hydroxy compound). In most cases the reaction product contains further oxidized compounds of type C or D, which, if desired, can be oxidized and then isolated in the form of the lactones I. The 18- ido-ZO-hydroxy compounds of the pregnane series obtained by this process are not very stable, wherefore it is of advantage not to isolate them as such, but to convert the crude reaction product into a stable compound first.

The crude 18-iodo-ZO-hydroxy-pregnanes can be treated for example with acylating agents, more specially with reactive derivatives of alpihatic, arali'phatic or aromatic carboxylic acids, whereby 18-iodo-20-acyloxy-preganes are obtained.

When an 18-iodo-20-hydroxy compound is reacted with a hydrolysing, more especially an alkaline agent, an 18:20-oxido compound is obtained (E). This conversion can be carried out with an inorganic or an organic base such as a hydroxide of an alkali or alkaline earth metal, for example sodium hydroxide, potassium hydroxide or barium hydroxide, or with silver oxide, an alkali metal carbonate such as sodium carbonate, potassium carbonate or calcium carbonate, triethylarnine, methyl piperidine, collidine, pyridine or the like. Even metal salts of carboxylic acids, such as potassium acetate, sodium propionate, silver acetate or the like can be used for forming the 18:20-oxido compounds; in this case an aqueous or anhydrous solvent is used such as an alcohol, for example methanol, ethanol or propanol, or an ether, for example tetrahydrofuran, dioxane, glycol dimethyl ether or the like, or pyridine, dimethylformamide or the like. In the case of iodine and mercury acetate or silver acetate, this conversion can in part be performed in the reaction mixture immediately following the formation of the 18-iodo-20-hydroxy compound in the polar solvent.

On the other hand an 18-halogeno-20-hydroxy-compound obtained by the present process can be oxidized, more especially in an acid solution, to formv the corre sponding 18-halogeno-20-oxo compound. Particularly suitable oxidants are compounds of hexavalent chromium, for example, chromium trioxide in glacial acetic acid or in acetone, with addition of sulfuric acid.

In an 18-iodo-20-oxo compound obtained in this manner the 18-iodine atom can be replaced hydrolytically by an oxygen function to yield a 20-hydroxy-18z20-oxido compound or a derivative thereof, that is to say a semiketal of an 18-hydroxy-20-oxo compound or a derivative thereof. The hydrolysis can be carried out as described above for the conversion of an l8-iodo-20-hyd'roxy compound into an 18:20-ether. When an alcohol is used as solvent it is very easy to prepare the 20-alkoxy-18:20- oxido compounds which can be split up to form 20-hydroxy-18z20-oxido compounds by acid hydrolysis, for example with aqueous mineral acid in a non-alcoholic medium (for example in dioxane).

The 18-iodo-18,20-oxido-pregnane compounds can easily be hydrolysed to the l8-hydroxy-l8z20-oxido COrnpounds, e.g., by the action of an aqueous solvent, for example, aqueous acetone, tetrahydrofuran or dioxane. It is especially advantageous to carry out the hydrolysis in aqueous acetic acid with the addition of an alkali metal acetate, for example, sodium acetate or potassium acetate. In this manner any acetals or ketals present are simultaneously converted into free aldehydes or ketals.

By treating the crude reaction product, which contains the l8-iodo-l8:20-oxido-compound, in a neutral medium, for example, in acetone or in dimethyl-formamide, with an alkali metal salt of carboxylic acid, for example, with potassium acetate, sodium propionate or potassium butyrate, there is obtained the corresponding 18-acyl0xy- 18:20-oxido-pregnane, from which the free l8-hydroxyl8z20-oxido-pregnane is obtained by acid or alkaline hydrolysis. In an analogous manner there are obtained by reacting the l8-iodocompounds with alkali metal alcoholates the 18-alkoxy-18:20-oxido-compounds.

The 18-acyloxy-18:20-oxido-compounds can also be obtained by esterifying the 18-hydroxy-l8:2O-oxido-c0mpounds with acylating agents in known manner. An advantageous method for obtaining the lS-alkoxy-compounds consists in reacting the 18-hydroxy-18:20-oxidocompounds with alcohols in the presence of an acid catalyst, such as hydrochloric acid, sulfuric acid or paratoluenesulfonic acid, if desired with addition of an orthoester, such as ortho-formic acid methyl ester, ethyl ester or the like. By reacting the 18-hydroxy-18z20-oxido pregnanes with dihydro-pyrane in the presence of an acid catalyst, such as para-toluenesulfonic acid or pyridine hydrochloride or the like, 18-tetrahydropyranyl others are obtained.

In the hydrolysis of the 18-iodo-l8220-oxido compounds, there are also formed in part bimolecular ethers, which are produced from 2 molecules of the l8-hydroxy- 18:20-oxido-compound with the loss of 1 molecule of Water, probably with the formation of an l8:18-oxygen bridge.

By treating the 18-hydroxy-18:20-oxido-compounds tially stable under the reaction conditions to be used in with acylating agents, for example, with acetic anhydride the present process. in the presence of a Lewis acid, such as boron trifluoride, The starting materials can be prepared, for example, by there are obtained l8:18:20-triacyloxy-derivatives, which reducing a suitable -ketone with hydrogen in the presare subjected to mild acid hydrolysis, for example, by 5 ence of a noble metal catalyst, for example platinum, or means of acetic acid, to form the 20-acyloxy-18-aldehydes. with a complex metal hydride such as sodium boro- The 18-aldehyde group can then be acetalized, the 20- hydride, lithium tri-tertiary butoxy aluminum hydride or acyloxy groups can be hydrolyzed under alkaline condithe like. An especially advantageous process for the tions, and the 20-hydroxygroup dehydrogenated to the manufacture of starting materials with a A -3-oxoor 20-oxo group, for example, by means of chromium tri- 1O A -3-ketal-grouping consists in the selective oxidation of oxide and pyridine. These reactions are represented by polyhydroxy-steroids. In this process a steroid with the following scheme of partial formulae: several oxi'dizable carbinol groups, some of which contain HO 0 CH3 AGO/OH3 i AGO/CH3 X X X 0/ 0 0/ \O no on 0/ ao on CH3 3 c 3 ME to Me ta we a As starting materials for the present process there are a double bond in the azfi-position, is treated in an arosuitable both ZOa-hydroXy and ZQB-hydroxy compounds matic hydrocarbon, e.g., benzene, toluene or xylene, with of the Su-pregnane and Sfi-pregnane series and of the a carbonyl compound, e.g., an aliphatic, alicyclic or arali- 19-nor or 21-nor pregnane series which may contain in phatic ketone or quinone, in the presence of a light metal the ring system-more especially in one or several of alcoholate, e.g., tertiary butylate or isopropylate of aluthe positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, minum or magnesium, until absorption in ultraviolet light 17, 2lfurther substituents such as functionally conreaches a maximum between 230 and 260 mg.

verted hydroxyl groups or free or functionally converted The 19-nor-20-hydroxy compounds are likewise preoxo groups, alkyl such as methyl groups, or halogen pared from suitable 19-nor-pregnane-20-ketones, more es atoms. The term functionally converted hydroxyl or pecially from 19-nor-progesterone and from the llot-hyoxo groups refers to esterified or etherified hydroxyl 0 droxy-19-nor-progesterone obtained therefrom by microgroups and ketalized oxo groups respectively. Furtherbiological hydroxylation in position 11a. Reduction of more, the starting materials may also contain double the last-named compound yields the corresponding polybonds or oxido groups, for example starting from carbon hydroxy steroid which, after the selective oxidation procatom 5 and/ or in position 9:11. Specific starting mateess mentioned above, yields a ZO-hydroxy-19-nor-pregnane rials are, for example, the following compounds: compound which may be used advantageously as starting material in the present process.

The l8-iodo-20-hydroxy-, 18-iodo-20-oxo-, 18-iodo-18, 20 oxido and 18-hydroxy-l8,20-oxido-pregnane compounds obtainable according to the present process and 3 [i :20-dihydroxy-5ot-p1'egnane,

3 ,8 ZO-dihydroxy- 1 l-oxo-Sa-pregnane,

3 6 ZO-dihydroxy-l lfi-acetoxy-S ot-pregnane, 3 ac ZO-dihydroxy-Sti-pregnane,

3 0c ZO-dihydroxy- 1 1-oxo-5 fl-pregnane,

3 u 20-dihydroxy-1 1 ,H-acetoxy-SB-pregnane, 3 ,8: 1 1m ZO-trihydroxy-S a-pregnane,

3 a: 1 1a:ZO-trihydroxy-SB-pregnane, A -3-oxo-1 1a-acetoxy-ZO-hydroxy-pregnene, A -3 -oxo-1 1 ,B-acetoxy-ZO-hydroxy-pregnene, A -3 11-dioxo-20-hydroxy-pregnene,

uents and/ or double bonds in the ring system as the corresponding above mentioned starting materials. Among these saturated and unsaturated pregnane compounds and their functional derivatives, such as the IS-esters, 18- ethers and l8-acetals, there are of especial importance those which are unsubstituted in the 17- and/ or 2l-posi- 419 11 tions or contain in those positions free, esterified or i i ggif g gg gggigfgfgifigx etherified hydr-oxyl groups. In the esters the acid radicals A46 oxo z0 hydroxy pregnene may be those of a lower aliphatic mono or dicarboxylic A56?zo dihydroxy pregnene 60 ac1d, preferablvhaving from 1 to 8 carbon atoms, such y p as acetic, propionlc, butyric, trimethylacetic, succinic,

' glutaric, glycollic and diglycollic acids, trifiuoroacetic acid as well as the 20-methyl-pregnanes obtained by reacting a or an aromatic carboxylic, preferably a monocyclic acid, Suitable -P ne with a methyl metal compound. such as benzoic acid, a monocyclic cycloaliphatic acid or In said starting materials the hydroxyl groups present in araliphatic acid, such as hexahydrophthalic acids, tetraaddition to the ZO-hydroxy group, for example, in 3- and/ hydrophthalic acids, cyclohexanoic acids, cinnamic acid,

or ll-position, are protected by esterification. -3- phenylpropionic acid, aliphatic or aromatic heterocyclic ketones can also be used in the form of their A -3-ketals. acids such as furan carboxylic acid,'nicotinic acid or also Surprisingly, under the reaction conditions to be used in of sulfonic acids, such as methane sulfonic acid, benzenethe present process, in contrast to the treatment with lead sulfonic, para-toluene sulfonic acid or the like. In the tetraacetate in the absence of iodine, methylene groups are ethers the alcoholic radical is preferably one derived from not or hardly at all affected simultaneously with ketones a lower aliphatic alcohol, such as methyl, ethyl, propyl, so that it is possible to use starting materials containing butyl, isopropyl, isobutyl alcohol or of an araliphatic alcofree keto groups, for example 3-ketones, A -3-ketones, 11- hol such as a monocyclic lower araliphatic alcohol, e.g.,

ketones or the like. A -3-ketones are likewise substan- 7 benzyl alcohol or of heterocyclic alcohols such as tetra- 50 their functional derivatives may contain further substitby the action of collidine; an lla-hydroxyl group can then be introduced in the compound so obtained by microbiological methods and there is also obtained the lactone of Formula HI.

hydroxyl group and which may be, e.g., saturated in rings A and B. The A -3-oxo group is formed in such a case during the above conversion at a suitable stage. The products of the process that are hydroxylated in position AGO--- A00 AcO--- ACO" 1( :+A 2 }Bya known (2) NaOH process CH 0 9 Hz. CH3

OH JJHOH AoO-- Hmfij L1AIH4 AcO 0 iCrOa In the latter compound there can be introduced a double bond in 4,5 position as stated above and the conversion into aldosterone is then made as shown in the preceding formulae scheme. Reactions by which final products of the process of the invention can be converted into intermediate products for the manufacture of aldosterone and related compounds are described in U.S. patent application Serial No. 74,487, filed December 8, 1960, by Charles Meystre et al., now U.S. Patent 3,121,080, in US. patent application Serial No. 74,470, filed December 8, 1960, by Oskar Jeger et al., and U.S. patent application Serial No. 74,488, filed December 8, 1960, by Charles Meystre et 211., now U.S. Patent 3,098,070. The conversion of the 18:20-oxides obtainable according to the present invention via the corresponding 18:20-lactones into aldosterone and its related compounds is also described in detail in Experientia 16, page 23, and Helvetica Chim. Acta 44, page 502 (1961).

From the 18-iodo-20-hydroxy pregnane compounds obtainable by the present process which are unsubstituted in ll-position and have an oxygenated substituent in 3- position, the known 18-hydroxy-progesterone can also be obtained easily. For instance, one may start from compounds which have already in 3-position a protected oxo group and a double bond in the :6-position. Oxidation is carried out with these derivatives in a manner analogous to that described in Example 31 herein, and there are thus obtained 18-iodo-20-oxo-compounds which may then be converted into the said 18-hydroxy-progesterone by reaction with e.g., silver acetate, followed by hydrolysis of the ester and liberation of the protected ketal group. However, one may also start from compounds which have in the 3-position, e.g.,v a free or esterified are also intermediates for the manufacture of 9afiuoro-lS-hydroxy corticosterone and 9m fluoro aldosterone.

The following examples illustrate the invention:

Example 1 A mixture of 1.0 gram of 3fi-acetoxy-20B-hydroxy- Su-pregnane, 6.0 grams of lead tetraacetate dried in a high vacuum, 2.0 grams of calcium carbonate and 2.0 grams of iodine is covered with 200 cc. of'cyclohexane. The suspension is stirred under reflux for 1 /2 hours under calcium chloride closure, then cooled and suctionfiltered. The filter residue is washed with ether, the filtrate is agitated with sodium thiosulfate solution and with water, and the organic solution is dried and evap orated in vacuo at first at 40 to 50 C. and then at 20 C.

The residue is treated with 2 grams of anhydrous sodium acetate and 40 cc. of dimethylformamide. The suspension is heated for 2 hours on a boiling water bath, evaporated in vacuo, the residue is agitated with ether, and the ethereal solutions are washed with water, dried and evaporated in vacuo. The residue is chromatographed on 30 grams of alumina (activity II). The first pentane eluates contain oily products. From the benzene fractions (610 mg.) a mixture of methanol and water yields 300 mg. of crystals of 3,8:18-diacetoxy-18:20B- oxido-Swpregnane melting at 141 to 144 C.

Infra-red spectrum in methylene chloride: bands inter alia at 5.80 (shoulder at 5.77), 8.10, 9.74 (acetate) and at 1034p.

From the evaporated ether fractions of the chromatography a mixture of ether and pentane yields a crystalline product, the 3B-acetoxy-20-hydroxy-18:20 oxido-5 x-pregnane, melting at 184 to 194 C.

200 mg. of the oxido compound obtained in this manner, melting at 141 to 144 C., are dissolved in cc. of acetic acid of 80% strength. The solution is heated for one hour on a boiling water bath, evaporated in vacuo, the residue is taken up in ether, and the solution is washed with dilute sodium carbonate solution and then with water, dried and evaporated in vacuo. The residue is recrystallized from a mixture of ether and pentane, to yield 35 acetoxy-lS-hydroxy-18:20-oxido-5a-pregnane melting at 175 to 190 C. Infra-red spectrum in methylene chloride: bands inter alia at 2.72 (hydroxyl), 5.77, 8.10 and 9.70 (acetate).

A solution of 100 mg. of this 18-hydroxy compound in 1 cc. of pyridine and 2 cc. of acetic anhydride is kept for hours at C., then treated with water, diluted with ether, and the ethereal solution is washed with dilute sodium carbonate solution and with water, dried and evaporated in vacuo. Recrystallization of the residue from aqueous methanol yields 3pzl8-diacetoxyl8z20-oxido-5a-pregnane melting at 141 to 144 C.

A solution of 100 mg. of 3 8-acetoxy-18-hydroxy- 18:20-oxido-5oc-pregnane in 2 cc. of methanol is treated with 1 drop of methanolic hydrochloric acid, the whole is kept for one hour at 20 and then evaporated in vacuo. The residue, the 3fl-acetoxy-18-methoxy-18:20-oxido-5apregnane, displays no hydroxyl band in the region of 2.72 1. in the infra-red spectrum in methylene chloride.

A suspension of 200 mg. of 3fl-acetoxy-18-hydroxy-18: 20-oxido-5a-pregnane in 6 cc. of acetic anhydride is mixed with 12 drops of boron trifluoride-ether complex and the Whole is shaken for 20 minutes, whereupon everything passes into solution. Ice is then added and the mixture is extracted with ether. The ether solution is washed with dilute sodium carbonate solution and then with water, dried and evaporated in vacuo. The residue is dissolved in 4 cc. of acetic acid of 80% strength.

The solution is heated for one hour on a water bath and then evaporated in vacuo. The residue is dissolved in ether, the ether solution is filtered through 6 grams of alumina (activity II) and evaporated in vacuo. In the infra-red spectrum in methylene chloride the resulting 3B:ZO-diacetoxy-l8-oxo-5a-pregnane displays bands inter alia at 3.70 (weak), 5.70 (aldehyde), 5.80, 8.10 and 9.75,u (acetate).

An analogous reaction of A -3fl-acetoxy-ZOB-hydroxypregnene with lead tetraacetate and iodine and sodium acetate in dimethylformamide yields A -3fl:18-diacetoxy- 18:20I3-oxido-pregnene which is hydrolysed With acetic acid of 60% strength to A -3 3-acetoxy-18-hydroxy-18: 20fi-oxidopregnene melting at 203 to 206 C. As a byproduct of this reaction there is obtained the corresponding bimolecular 18:18'-ether which melts at 285 to 290 C. This ether can be split again to the 18-hydroxy-18:20-oxido compound by treatment with perchloric acid in tetrahydrofuran.

Reaction of the 18-hydroxy-18120fi-oxido compound with methanolic hydrochloric acid furnishes A -3B-acetoxy-18-methoxy-18 :20p-oxidopregnene.

Example 2 6 grams of lead tetraacetate dried in a high vacuum at 20 C., 2 grams of iodine and 2 grams of dry calcium carbonate are covered with 200 cc. of cyclohexane. The suspension is stirred for one hour under reflux and calcium chloride closure. 1 gram of A -3-ethylenedioxy 11a-acetoxy-ZOB-hydroxypregnene is then added, and the mixture is refluxed for another 6 hours, then cooled, and the inorganic salts are suctioned off and washed with ether. The solution is then diluted with ether and agitated with sodium thiosulfate solution and with water. The ethereal solutions are treated with 2 grams of sodium acetate and 50 cc. of acetic acid of 80% strength, and the ether is distilled off on a water bath. The remaining acetic acid solution is heated for another 2 hours on a boiling water bath, considerably concentrated in vacuo and the residue is taken up in ether and water. The ethereal solution is washed with dilute sodium carbonate solution and with water, dried and evaporated. The residue (1.05 grams) contains A -3-oxo-11a-acetoxy-18- hydroxy-18:20fi-oxidopregnene which is covered with a solution of 1 gram of potassium carbonate in 10 cc. of water and 50 cc. of methanol. The resulting solution is refluxed for 5 hours, then considerably concentrated in vacuo, the residue is taken up in ethyl acetate and Water, the ethyl acetate solution is Washed with dilute sodium carbonate solution and water, dried and evaporated in vacuo. Yield: 710 mg. of crude A -3-oxo-l1a:18-dihydroxy-18 :20fi-oxidopregnene.

Example 3 As described in Example 2, 1 gram of A -3-ethylenedioxy-lla acetoxy 20B hydroxypregnene is converted into A -3-oxo-11a-acetoxy-18-hydroxy-18:20B oxidopregnene. The 1.05 grams of this compound thus obtained are covered with 15 cc. of ethylene glycol, 100 cc. of benzene and 50 mg. of paratoluenesulfonic acid. The solution is refluxed for 8 hours, using a water separator. The cooled solution is diluted with ethyl acetate, washed With dilute sodium carbonate solution and water, dried and evaporated in vacuo. The residue (1.16 grams) is chromatographed on 30 grams of alumina (activity II). The fractions obtained with a lzl-mixture of benzene and pentane display no hydroxyl band at 2.75u. On the other hand, the subsequent benzene fractions and ether fractions (total residue 660 mg.) display in the infrared spectrum in methylene chloride a strong hydroxyl band at 274 further bands at 5.80, 8.06 and 9.73 1. (acetate) and a broad band between 9.98 and 920 with a maximum at 8.98 1. The compound thus obtained is A -3:IS-bisethylenedioxy-lIa-acetoxy-ZOfl hydroxypregnene.

Example 4 A mixture of 1 gram of A -3-ethylenedioxy-20,B- hydroxypregnadiene, 6 grams of lead tetraacetate dried in a high vacuum, 2 grams of dry calcium carbonate and 2 grams of iodine is covered with 200 cc. of cyclohexane. The suspension is stirred for 6 hours under reflux and calcium chloride closure, cooled, the insoluble share is suctioned off and Washed on the filter with ether. The filtrate is washed with sodium thiosulfate solution and water, dried, treated with 2 grams of dry sodium acetate and evaporated in vacuo. The residue is treated with 50 cc. of acetic acid of strength, heated on a boiling Water bath, evaporated in vacuo, the residue is taken up in ether, and the ether solution is washed with dilute sodium carbonate solution and with water, dried and evaporated in vacuo. The resulting crude A -3-oxo- 18 hydroxy 18:20,8 oxidopregnadiene displays in the infra-red spectrum in methylene chloride bands, inter alia, at 2.70 (hydroxyl), 6.00 and 6.22 (A -3-ketone).

Example 5 By the method described in Example 4 A -3,8:21-diacetoxy-20fl-hydroxypregnene can be converted into 11 -35:21-diacetoxy-18-hydroxy 182205 oxidopregnene which displays in the infra-red spectrum in methylene chloride bands, inter alia, at 2.72 (hydroxyl) and at 5.82, 8.09, 9.74 (acetate).

Example 6 In a manner analogous to that described in Example 4 A -2OB-hydroxy-pregnadiene-3-one can be converted into the corresponding A -18-hydroxy-18:2O-oxido-pregnadiene-3-one which in the infra-red spectrum in methylene chloride displays bands, inter alia, at 2.73 (hydroxyl), 6.02, 6.16 and 6.23;; (A -3-ketone).

The starting materials mentioned in Examples 1 to 6 are obtained by reducing the appropriate 20-keto compounds. The 20-hydroxypregnane compounds used in Examples 2, 3 and 4 can be obtained, for eXample, as follows:

lla-acetoxy-progesterone is converted by reduction with sodium borohydride in methanol and selective oxida tion with bromacetamide in benzene-l-pyridine into the A -3-oxo-11a-acetoxy-ZO-hydroxypregnene which, on ketalization with ethylene glycol and para-toluenesulfonic acid in benzene, furnishes A -3-ethylenedioxy-l1a-ace toxy-20-hydroxypregnene. An analogous reaction of A -3:20-dioxopregnadiene furnishes A -3-ethylenedioxy-20-hydroxypregnadiene.

Example 7 A mixture of 6 grams of lead tetraacetate dried in a high vacuum, 2.2 grams of iodine and 2 grams of calcium carbonate is covered with 200 cc. of cyclohexane. The suspension is stirred under reflux for 30 minutes with exclusion of moisture. 1 gram of 3;8-acetoXy-l6a-methyl- ZOfl-hydIOXy-Suregnane is then added and the reaction mixture is boiled for 6 hours, cooled, the insoluble salts are suctioned oflt' and washed with ether. The filtrate is washed with sodium thiosulfate solution and with water, dried and treated with 2 grams of dry sodium acetate. After evaporation of the solvent mixture in vacuo, the residue is dissolved in 50 cc. of acetic acid of 80% strength, heated for 2 hours on a boiling water bath and evaporated. The residue is agitated with ether, and the ethereal solution is washed with water, then with dilute sodium carbonate solution and then with water, dried and evaporated in vacuo. The resulting 3 6-acetoxy-18- hydroxy-18:20p-oxido-16a-methyl 5oz pregnane displays in the infra-red spectrum in methylene chloride bands, inter alia, at 2.73 (hydroxyl), 5.81, 8.09, and 9.74 '(acetate).

The starting material is obtained by catalytic reduction (platinum-glacial acetic acid) of 3fi-acetoxy-16amethyl-ZO-oxo-Su-pregnane.

Example 8 60 grams of lead tetraacetate are freed from acetic acid at room temperature in a desiccator during about 30 minutes in a water jet vacuum, then during another about 30 minutes in a high vacuum, and then heated to the boil with stirring with 20 grams of dried calcium carbonate and 1.8 liters of cyclohexane. 16 grams of iodine are then added and the mixture is boiled for one hour. grams of A -3-ethylenedioxy-l1a-acetoxy-20B-hydroxypregnene are then added, and the suspension is refluxed for 4 hours, cooled to room temperature and suction-filtered. The residue is thoroughly washed with ether.

The filtrate is washed at 0 C. with sodium thiosulfate solution and then with water, dried, poured into 30 grams of anhydrous sodium acetate and 100 cc. of dimethylformamide, and the solution is concentrated in vacuo. The remaining dimethylformamide solution is :diluted with 10 0 cc. of dimethylformamide and heated for 2 hours on a boiling water bath. The dimethyltormamide solution is then considerably concentrated in vacuo at about 90 to 95 C, cooled, and diluted with water.

18 :20-oxidopregnene.

The resulting crude diacetate is treated with 10 grams of potassium canbonate, 100 cc. of water and 400 cc of methanol and the solution is refluxed for one hour. Water is then added and the methanol is removed by distillation in vacuo and the residue is agitated with ether.

The ethereal solution is washed with Water, dried and evaporated. The residue is crystallized from about 50 cc.

' of freshly distilled isopropyl ether. The crystals are suctioned off, thoroughly washed with isopropyl ether and 'dried. The concentrated mother liquors yield further alumina.

14 amounts of crystals. The total yield amounts to 6.2 grams of A -3-et'hy-lenedioxy-l'la-acetoxydS-hyd-roxy- 18:20-oxido'pregnene melting at 202 to 208 C. By chromatography of the mother liquors (4 to 5 grams) on grams of alumina further amounts of these compounds can be obtained from the ether eluates.

In a completely analogous manner there is obtained from 725 mg. of A -3-ethylenedioxy-2Oa-hydroxypregnene by treatment with lead tetraace tate and iodine aS described above, via the A 3-ethylenedioxy-18-iodo- 1*8:20a-oxidopregnene, 610 mg. of A -3-ethylenedioxy- 18 hydroxy-1 8 :20a-oxidopregnene.

A -3-ethylenedioxy-2Oa-hydroxjfipregnene is obtained by reducing the progesterone-3-monoketal with sodium and alcohol, which is then purified by chromatography on A -3-ethylenedioxy-2i0a-hydroxypregnene melts at to 178 C. Optical rotation [a] =-4'3 (in chloroform) Example 9 6 grams of lead tetra-acetate are dried for 30 minutes in a water jet vacuum and then for 30 minutes in a high vacuum. 2 grams of calcium carbonate and 200 cc. of cyclohexane. are added and the mixture is heated to the boil with stirring, then treated with 1.6 grams of iodine and refluxed for another hour. The boiling solution is then treated with 1 gram of A 3-ethylenedioxy-l0fi hydroxyapregnadiene, flushed with 12 cc. of cyclohexane and boiled for another 4 hours while being stirred. The reaction mixture is cooled, filtered, and the filter residue is washed with absolute ether. The filtrate is washed with an ice-cold solution of 5 grams of sodium thiosulfate in 20 cc. of water and then three times with water, whereupon the aqueous solutions are agitated twice wit-h ether. The combined organic solutions are evaporated in a flask containing 3 grams of sodium acetate and 3 grams of glacial acetic acid in a water jet vacuum at a bath temperature of 50 C. The residue is then treated with 30 cc. of acetic acid of 80% strength, heated for 2 hours on a boiling water bath, cooled, and evaporated in a water jet vacuum almost to dryness. Ether is added and the whole is washed successively with water, 2 N-sodium carbonate solution and water, dried and once again evaporated in a water jet vacuum. The residue contains A :9 -3-oxol 8 hydroxy-1 8 20oxidopregnadiene.

Example 10 6 grams of lead tetraacetate are dried for 30 minutes in a water jet vacuum and then for 30 minutes in a high vacuum. 2 grams of calcium carbonate and 200 cc. of .cyclohexane are added and the mixture is heated with stirring to the boil, treated with 1.6 grams of iodine and refluxed for another hour. There is added 1 gram of A -3-ethylenedioxy l lot-a-cetoxy-2OB-hydroxypregnene to the boiling solution, flushed with 12 cc. of cyclohexane, and boiled for another 4 hours while being stirred, then cooled, filtered and the filter residue is washed with absolute ether. The filtrate is Washed with an ice-cold solution of 5 grams of sodium thiosulfate in 20 cc. of water and three times with Water, whereupon the aqueous solutions are agitated twice with ether. The combined organic solutions are evaporated at a bath temperature of 24 C. in a Water-jet vacuum, whereupon a pale yellow oil is obtained which contains A -3-ethylenedioxy-1laacetoxy-l 8-iodo-l8 20-oxidopregnene.

Example 11 A solution of 800 mg. of A -3-ethylenedioxy-11a:18 dihydroxy-lS:QOfl-oxidopregnene in 20 cc. of absolute methanol is treated with 5.0 cc. of 2 N-methanolic hydrochloric acid and kept for 24 hours at 25 C. The reaction mixture is then evaporated to dryness in a waterjet vacuum and the residue, which contains the A -3-oxo- 1lot-hydroxyd8-methoxy-l8:20-oxid-opregnene, is taken up in 5 cc. of pyridine; 600 mg. of para-toluenesul fonic acid are added, and the mixture is kept for 48 hours 3.5 at room temperature, then poured into 100 cc. of icewater and repeatedly extracted with methylene chloride- The extracts are successively washed with N-hydrochloric acid, sodium bicarbonate solution and water, then dried and evaporated. The residue (950 mg.) is dissolved in 50 cc. of acetic acid of 80% strength and heated for 1 minutes at 100 C., whereupon the solution is evaporated to dryness in a water-jet vacuum. The residue consists of crude A -3-oxo-l'1a-tosyloxy-l8-hydroxyd8:ZOfi-oxidopregnene.

Example 12 A mixture of 1.0 gram of dry calcium carbonate, 3.0 grams of dry lead tetraacetate and 100 cc. of dimethylcyclohexane is heated to 80 C., 800 mg. of iodine are added and the whole is stirred for almost one hour at 80 C. 500 mg. of A -3-ethylenedioxy-1la-a-cetoxy-QOB- hydroxy-pregnene are then added and the mixture is stirred [for 4 hours at a bath temperature of 150 C., then cooled, filtered, and the filtrate is worked up as described in Example 3. 1.5 grams of sodium acetate and 5 cc. of glacial acetic acid are then added, the mixture is evaporated, heated for 2 hours at 100 C. with cc. of glacial acetic acid of 80% strength and then worked up, to yield 790 mg. of crude A -3-oxo-1 1a-acetoxy-1-8-hydroxy- 18 20-oxidopregnene.

Example 13 6.0 grams of lead tetraacetate containingacetic acid are dried in a water-jet vacuum and then in a vacuum of 0.1 mm. Hg and thereupon added to a suspension of 2.0 grams of dry calcium carbonate in 200 cc. of cyclohexane. The mixture is heated to the boil, 1.6 grams of iodine are added and the whole is refluxed for one hour. 1.0 gram of A -3-ethylenedioxy-9:11/8-oxido-20fi-hydroxypregnene is then added and the solution is boiled for another 3 hours with irradiation with a 500 watt lamp. During the reaction period the solution loses its color completely. After cooling, the undissolved salts are filtered off and the residue is thoroughly washed with ether. The filtrate is washed with sodium thiosulfate solution and then with water and evaporated in a water jet vacuum at a bath temperature of to C. The residue is crude A -3-ethylenedioxy-92115,18:ZOB-bisoxido-IS- iodopregnene.

Example 14 A stirred suspension, heated at 80 C., of 26 grams of dry lead tetraacetate and 8.8 grams of calcium carbonate in 1.2 liters of cyclohexane is treated with 7.2 grams of iodine and the violet mixture is refluxed for one hour. After cooling to about 60 C., 3.80 grams of A -3-oxo- 11a-acetoxy-20fl-hydroxypregnene are added and the whole is stirred for 4 hours while being heated with a reflector burner. The cooled, colorless reaction mixture is filtered, the filter residue is flushed with ether, and the filtrate is agitated once with a solution of 20 grams of sodium thiosulfate in 80 cc. of water and then three times with water. Without drying the solution it is evaporated in vacuo in a flask containing 12 grams of sodium acetate and 12 cc. of glacial acetic acid, and the residue is treated with 120 cc. of acetic acid of 80% strength and then heated for 2 hours at 100 C. The reddish reaction mixture is treated with 20 cc. of water and evaporated in vacuo. The residue is taken up in ether+water, washed with sodium bicarbonate solution and then with water until the washings run neutral, dried and evaporated; it is crude A 3-oxo-11a-acetoxy-18-hydr0xy-18:ZOB-oxidopregnene.

Example 15 A suspension of 1 gram of calcium carbonate and 3 grams of lead tetraacetate (dried for /2 hour in a water jet vacuum and then for /2 hour in a high vacuum) in 100 cc. of cyclohexane is boiled for a short time and then treated with 0.800 gram of iodine. After heating for one hour at C., 490mg. of A -3-ethylenedioxy-ll-oxo- ZOdhydroxypregnene are added. The reaction mixture is heated with stirring for another 4 hours at 80 C., and then filtered; the residue is washed with ether and the filtrate is washed with a solution of 2.5 grams of sodium sulfate in 10 cc. of water and three times with water. The organic solution is then evaporated in vacuo in a flask containing 1.5 grams of sodium acetate and 1.5 cc. of glacial acetic acid. The residue is treated with 15 cc. of acetic acid of 80% strength, heated for 2 hours at C., the solvent is evaporated in vacuo and the residue is worked up as described in Example 14, to yield 455 mg. of a yellowish oil, being crude 13 -3:l1-dioxo-18-hydroxy- 18 :20B-oxidopregnene.

In a completely analogous manner 960 mg. of A 3- ethylenedioxy-l1-oxo-20a-hydroxypregnene yield 920 mg. of crude A -3: 1-l-dioxo-18-hydroxy-l8 20a-oxidopregnene.

Exam le 16 A mixture of 9.0 grams of lead tetraacetate, 3.0 grams of calcium carbonate and 270 cc. of cyclohexane is heated to the boil while being stirred with exclusion of water, then 2.4 grams of iodine are added, and the whole is refluxed for one hour. 1.5 grams of A -3-ethylenedioxy- 1ia-acetoxy-ZOfi-hydmxy-l9-nor-pregnene are then added and the whole is boiled with stirring and while being irradiated with a 250 watt lamp until the color of iodine has completely disappeared. The reaction mixture is cooled to 20, filtered and the filter residue is washed with ether. The filtrate is Washed with cold sodium thiosuliate solution and then with water, the organic solution is dried, 4.5 grams of anhydrous sodium acetate and 15 cc. of dimethylformamide are added, and the volatile solvents are distilled off in a water-jet vacuum. The remaining dimethylformamide solution is treated with another 15 cc. of dimethylformamide and then heated for 2 hours at 100 C, The mixture is then evaporated in a water-jet vacuum, cooled, diluted with water and the precipitate formed is taken up in ether. The ether extract is washed with water and filtered through a column of 15 grams of alumina; the column is thoroughly washed with ether and the filtrate is evaporated to dryness, to yield 1.6 grams of crude A -3-ethylenedioxy-1la:18-diacetoxy-18z20-oxido-19-norpregnene. The crude product is dissolved in 60 cc. of methanol, mixed with a solution of 3.0 grams of potassium carbonate in 20 cc. of water, and the whole is refluxed for 3 hours under nitrogen. Another 20 cc. of water are added, the methanol is evaporated in a waterjet vacuum and the residue is repeatedly extracted with methylene chloride. The dried extracts are evaporated and yield 1.4 grams of a pale-yellow residue containing as the main product A -3-ethylenedioxy-11a:18-dil1ydroxy- 18 20oxidol9-norpregnene.

Example 17 30 grams of lead tetraacetate dried in a water-jet vacuum are heated for 1 hour with stirring in 1 liter of cyclohexane with 10 grams of dry calcium carbonate. 8.0 grams of iodine and 10.0 grams of 3fizlla-diacetoxy-2oflhydroxy-Sa-pregnane (M.P. to 166 C.) are added and the whole is boiled with stirring and while being irradiated with a SOD-watt lamp for another 100 minutes. After cooling, the undissolved salts are filtered ofl, the residue is washed with cyclohexane, the filtrate is agitated with sodium thiosulfate solution and with water, 2.5 cc. of pyridine are added, and the whole is evaporated to dryness in a water-jet vacuum. The residue is crude 35:11adiacetoxy-18-iodo-l8 20-oxido-5a-pregnane.

When a solution of the crude product obtained by the lead tetraacetate-oxidation in acetone is kept for 18 hours at 10 to 15 C., part of the 3B:11a-diacetoxy-18-iodo- 18:20fi-oxido-5a-pregnane present is converted into the bimolecular 18: 18'-ether of 3,8:1la-diacetoxy-l8-hydroxy- 18:20B-oxido-5a-pregnane which is easy to separate from the lactone formed after oxidation of the unreacted 18- 17 hydroxy or 18-iodo compound respectively with chromic acid-l-sulfuric acid.

The ether crystallizes from methanol in coarse crystalline prisms melting at 305 to 308 C. Optical rotation [a] =+35 (in chloroform). Infra red spectrum: no hydroxyl band. Bands, inter alia, at 5.77, 7.25, 8.09, 9.17, 9.76 and 1038p.

When this compound is hydrolyzed with potassium carbonate in methanol, the bimolecular 18:l8-ether of 313: 11a:18-trihydroxy-18:ZOQ-oXido-Su-pregnane is obtained which melts at 297 to 300 C.

When the above acetoxy ether (M.P. 305 to 308 C.) is treated with 4 N-aqueous perchloric acid in tetrahydrofuran, 3a! 11a diaceto-xy 18 hydroxy-18:20,8-oxido-5apregnane is obtained.

The 3,3:11a-diacetoxy-ZOfi-hydroxy-Swpregnane used as starting material in this example is obtained by reducing the appropriate 20-ketone with lithium-tri-tertiary butoxyaluminum hydride in tetrahydrofuran.

In a completely analogous manner 3a:11a-diacetoxy- ZOfl-hydroxy-SB-pregnane (melting at 155 to 156; optical rotation [a] =5 prepared by catalytic hydrogenation of the appropriate 20-ketone with platinum in glacial acetic acid) yields 3m:11a-diacetoxy-18-iodo-18:ZOB-oxido-SB-pregnane which is easy to hydrolyze to 3azlla-diacetoxy-18-hydroxy-18 20,B-oxido-5fl-pregnane.

Example 18 A suspension of 60 grams of dried lead tetraacetate and 20 grams of dry calcium carbonate is heated to the boil while being stirred. After one hour the mixture is treated with 16 grams of iodine and grams A -3-ethylcnedioxy- 11a-acetoxy-20ot-hydroxypregnene and flushed with 7 0 cc. of cyclohexane. The mixture is then stirred for 2 hours under reflux while being irradiated with a 5 00-watt lamp. After cooling, the undissolved salts are suctioned 01f, the residue is washed with 750 cc. of cyclohexane and the filtrate is agitated with an ice-cold solution of 50 grams of sodium thiosulfate in 200 cc. of water. The reaction solu-- tion is washed twice with 200 cc. of water, treated with 5 cc. of pyridine, dried with sodium sulfate and evaporated in a water-jet vacuum at a bath temperature of 35 C. The resulting product is crude A -3-ethylenedioxy-11uacetoxy-18-iodo-l 8 20a-oxidopregnene.

Example 19 As described in Example 18, 15.0 grams of A -3,B-acetoxy-2OB-hydroxypregnene (melting at 164 to 166 C.) are oxidized in 3 liters of cyclohexane with 90 grams of lead tetraacetate and 30 grams of calcium carbonate while being irradiated. Usual Working up yields a crude product which contains A -3fl-a'cetoxy-18-iodo-18:ZOB-oxidopregnene.

. The A -3,8-acetoxy-ZUri-hydroxypregnene (melting at 164 to 168) used as starting material in this example is obtained in a yield of about 64% from pregnenolone acetate by reduction with lithium-tri-tertiary butoxy-aluminum hydride in tetrahydrofuran and crystallization of the crude product from acetone.

Example 20 A suspension of 10.0 grams of mercury diacetate, 3.0 grams of calcium carbonate and 2.5 grams of 3B21lzx-(liacetoxy-20fl-hydroxy-Sa-pregnene in 200 cc. of cyclohexane is heated to the boil. After 30 minutes 11.0 grams of iodine are added and the whole is heated while being stirred and irradiated with a 500 watt lamp for an hour longer, during which time yellow mercury iodide separates out. The reaction mixture is then cooled, the precipitate suctioned off and washed with cyclohexane, and the filtrate is agitated with potassium iodide solution of 5% strength, with addition of sodium thiosulfate, until it loses its color, then washed with water, and the cyclohexane solution is dried and evaporated in a water-jet vacuum. The oily residue (6.40 grams) containing the 3fi:11a-diacetoxy-l8- iodo-18:ZOfi-oxido-Sa-pregnane is dissolved in 50 cc. of acetone, treated with 1.25 grams of silver chromate and stirred for 30 minutes at room temperature, then cooled to +5. C. and treated with 2.95 cc. of a solution of 13.3 grams of chromium trioxide in 11.5 cc. of concentrated sulfuric acid, made up with water to 50.0 cc. After one hour a solution of 28 grams of crystalline sodium acetate in 50 cc. of water is added, and the whole is diluted with benzene and washed with water. The benzene solution is dried, filtered and evaporated in a water-jet vacuum. The crude product is crystallized from ether and yields 595 mg. of the 18:20-lactone of 3,8211oc-dl3Cfit0XY-2OB- hydIoXy-Sa-pregnane-18-acid melting at 216-218 C. Optical rotation [a] =-23 (in chloroform). Infra-red bands, inter alia, at 5.69 1. ('y-lactone); 5.77p (acetates); 8.09, 8.75, 9.74 and 10.44,u..

The mother liquor is evaporated to dryness and the residue is chromatographed on grams of alumina. 600 cc. of a 4:1-mixture of hexane and benzene elute oily compounds (predominantly cyclohexanol acetate). From the fractions eluted with 600 cc. of hexane+benzene 1:1 there are obtained by crystallization from ether 89 mg. of 36:11u-diacetoxy-l7-iodo-5ot-androstane melting at 212- 214 C. Optical rotation [a] +=l9 (in chloroform). The following 200 cc. of benzene elute only oily compounds, whereas the second benzene fraction (200 cc.) yields on crystallization from ether 74 mg. of 382110:- diacetoxy-l8:20fl-oxido-5oc-pregnane melting at 140-142 C. The following fraction (200 cc. of benzene) contains a mixture of this compound with the following lactone; a further 400 cc. of benzene and 400 cc. of a 19:1-mixture of benzene and ethyl acetate yield another 276 mg. of the 18:20-lactone of 3,8:11a-diacetoxy-ZOfl-hydroxy-Su-pregnane-lS-acid melting at 216-218" C.

Example 21 2.5 g. of 3B:11ot-diacetoxy-20fi-hydroxy 5a pregnane and 5.0 g. of crystalline silver acetate are suspended in 200 cc. of cyclohexane, and the mixture, after the addition of 3.5 g. of iodine, boiled for 3 hours while being stirred and irradiated with a 500 W. lamp. During this operation the color of the iodine disappears nearly completely, and a yellow precipitate of silver iodide is formed. The reaction mass is then cooled, the insoluble salts filtered off, and the filter rinsed with cyclohexane. The filtrate is decolor: ized by washing with sodium thiosulfate solution, dried, and evaporated in a water jet vacuum.

The resulting crude product (3.46 grams) is dissolved in 50 cc. of acetone, treated with 1.25 grams of silver chromate and then stirred for 30 minutes at room temperature, cooled to 0 C., and 2.95 cc. of a solution of 13.3 grams of chromium trioxide in 11.5 cc. of concentrated sulfuric acid, made with water up to 50 cc. After one hour 28 grams of crystalline sodium acetate in 50 cc. of water are added and the reaction mixture is worked up as described in Example 20. The crude product (3.173 grams) yields on crystallization from ether+pentane 478 mg. of crystals (melting at 124-l26 C. with decomposition) containing about 50% of 3p:11a-diacetoxy-lS-iodo-ZO- oXo-5a-pregnane and about 50% of 3B:11u-diacetoxy-20- OXo-Sa-pregnane. The mother liquor is evaporated to dryness, the residue is dissolved in cc. of acetone, mixed with 3.35 grams of potassium acetate and 3.3 cc. of glacial acetic acid, and the whole is refluxed and stirred for 8 hours at a bath temperature of 80 C., then cooled, evaporated in a water-jet vacuum almost to dryness, and the residue is taken up in methylene chloride and water. The extract is washed with water, dried and evaporated, to yield 2.970 grams of a crude product which on crystallization from ether yields 23 5 mg. of 3B:llu-diacetoxy-20-oxo-5apregnane melting at 172-174 C. The mother liquor is evaporated and the residue is chromatographed on 80 grams of alumina. Elution with 600 cc. of benzene+hexane 4:1 and with 600 cc. of benzene+hexane 1:1 furnishes only oily products. From the benzene fraction (800 cc.)

19 another 555 mg. of 3 8:11a-diacetoxy-20-oxo-5a-pregnane can be obtained. Elution with the following 400 cc. of benzene-i-ethyl acetate 14:1 furnishes a total of 385 mg. of a substance from which by crystallization from ether the 18:20-lactone of 3p:11cx-diacetoxy-20/3-hydroxy-5apregnane-18-acid, melting at 216-218" C. can be isolated.

Example 22 A suspension of 500 mg. of 3mzllot-diacetoxy-20p-hydroxy-5,8-pregnane in 50 cc. of methyl cyclohexane is treated with 1.80 grams of silver acetate and 1.22 grams of iodine, and the mixture is refluxed for 10 hours at a bath temperature of 120 C. with exclusion of moisture, and allowed to cool. The precipitated silver iodide is suctioned off, washed with ethyl acetate, and the filtrate is washed with solutions of potassium iodide and sodium sulfite, and the aqueous extracts are extracted with ethyl acetate. The solutions are dried and evaporated in a water-jet vacuum and yield .686 mg. of an oil which, according to its chromatographic analysis, contains in addition to starting material a small amount of 3a: Ila-diacetoxy -20-oxo-5/3-pregnane and the 3 a: llot-diacetoxy-lfi 20- oxido-pregnane. Before subjecting it to purification, the residual starting material is oxidized to convert it into the aforementioned ZO-ketone; for this purpose the crude product is dissolved in 10 cc. of glacial acetic acid, a solution of 200 mg. of chromium trioxide in 2.0 cc. of water is added, and after 2.5 hours the whole is diluted with benzene and then washed with sodium sulfite solution, sodium bicarbonate solution and Water, and the benzolic solution is then dried and evaporated in a water-jet vacuum. Yield: 570 mg. of a residue which crystallizes on being moistened with ether.

The above crude product is purified by chromatography on 40 grams of alumina. Hexane-I-benzene mixture 9:1, 4:1 and the first 1:1 mixtures elute weakly polar byproducts. A total of 200 cc. of benzene-l-hexane mixture 1:1 and 300 cc. of undiluted benzene then elute 205 mg. of 3a:11a-diacetoxy-l8:20-oxido-5/3-pregnane which is still contaminated m'th a small amount of 3uzlla-diacetoxy-20-oxo-pregnane and, after having been recrystallized from ether-i-pentane and methanol, melts at 155-158 C. The last benzolic fractions contain predominantly the 20-ketone.

Since it is very difficult to prepare completely pure 3a:-11oc-diacetoxy 18:20 oxido-Sfi-pregnane, the crude crystalline product (205 mg.) is dissolved in 10 cc. of acetanhydride, treated at C. with a mixture of 0.45 cc. of acetanhydride and 0.15 cc. of boron trifluoride etherate, and the whole is stirred for 20 minutes at 0 C. 200 mg. of crystalline sodium acetate are then added, the mixture is evaporated to dryness in a water-jet vacuum, and the residue is taken up in methylene chloride. The methylene chloride solution is washed with water, dried and evaporated. The residue (241 mg.) is purified by filtration through alumina. A 1:1 mixture of benzene+hexane elutes crystalline by-products, whereas the fractions (140 mg.) eluted with undiluted benzene yield pure 3a:11a:18:20a-tetraacetoxy-S S-pregnane melting at 15 8-1 60 C.

Example 23 A suspension of 1.0 gram of mercuric acetate in 25 cc. of methyl cyclohexane is treated with 800 mg. of iodine and 250 mg. of 3a:11a-diacetoxy-20p-hydroxy-5p-pregnane, and the mixture is boiled for 6 hours at 120 C. with exclusion of moisture, during which operation red mercury iodide separates out. The mixture is cooled, the precipitate suctioned off, rinsed on the filter with ethyl acetate, and the filtrate is washed with potassium iodide solution, sodium sulfite solution and with water. When the organic solution is dried and evaporated, 1.10 grams of a product containing mercury result. The latter product is dissolved in cc. of glacial acetic acid, 500 mg. of potassium acetate and 1.0 cc. of water are added, and

20 the mixture is heated for 30 minutes at C., then poured into water, extracted with methylene chloride, and the extracts are washed with water, dried and evaporated to dryness in a water-jet vacuum.

To convert the residual starting material into the 20- ketone, the residue (391 mg.) is oxidized with chromium trioxide in aqueous glacial acetic acid .as described in Example 22. There are obtained 314 mg. of a crude product which can be crystallized from ether and, according to its chromatographic examination, contains 3azlladiacetoxy-18:ZO-oxido-Sfl-pregnane in addition to 30a! 11adiacetoxy 20 oxo-SB-pregnane. The crude product is purified as described in Example 22.

Example 24 A mixture of 250 mg. of 3a:11a-diacetoxy-20;3-hydroxy-SB-pregnane, 25 cc. of methyl cyclohexane, 500 mg. of calcium carbonate and 400 mg. of iodo-succinicide are refluxed for 6 hours at a bath temperature of 120 C. with exclusion of moisture. Iodine separates out copiously during the reaction, and the solution turns brownviolet. After cooling, the precipitate is filtered off, rinsed on the filter with benzene, and the filtrate is washed with dilute sodium thiosulfate solution and with water. The organic solution is dried and evaporated in a water-jet vacuum; the crude product (291 mg.) is revealed by its chromatographic analysis to contain 3a:11a-diacetoxy- 18:20-oxido-5fi-pregnane, in addition to starting material and a large amount .of weakly polar products.

Example 25 A suspension of 750 mg. of silver acetate in 50 cc. of benzene is mixed with 570 mg. of iodine and stirred for 1 hour at room temperature, whereupon nearly all iodine has disappeared, and the reaction mixture contains in the yellow solution the silver acetate-Hodine complex in addition to precipitated silver iodide. 420 mg. of A -3-ethylenedioxy-l1a-acetoxy-20,B-hydroxy-pregnene are then added .and the whole is refluxed for 5 hours at a bath temperature .of C. with exclusion of moisture. The reaction mixture is allowed to .cool, the silver iodide is suctioned off, and the filtrate is washed with water. Evaporation of the dried benzolic solution in a water-jet vacuum yields 500 mg. of a yellow foam which is revealed by its chromatographic analysis to contain A -3-ethylenedioxy-l lot-acetoxy 18:20 oxido-pregnene in addition to starting material and a weakly polar by-product. By chromatography on alumina, mg. of the pure compound can be isolated; it melts at 167-l69 C.

Example 26 A suspension of 10.0 grams of mercury diacetate, 3.0 grams of calcium carbonate and 2.5 grams of 3131110:- diacetoxy-ZOp-hydrOXy-Sa-pregnane in 200 cc. of cyclohexane is heated to the boil. After 30 minutes 11.0 grams of iodine are added and the whole is heated while being stirred and irradiated with a 500 watt lamp for an hour longer, during which time yellow mercury iodide separates out. The reaction mixture is then cooled, the precipitate suctioned off and washed with cyclohexane, and the filtrate is agitated with potassium iodide solution of 5% strength, with addition of sodium thiosulfate, until it loses its color, then washed with Water, and the cyclohexane solution is dried and evaporated in a waterjet vacuum. The oily residue (6.40 grams) containing the 313:1la-diacetoxy-l8-iodo-l8z20fl-oxido-5a pregnane is dissolved in 50 cc. of acetone, treated with 1.25 grams of silver chromate and stirred for 30 minutes at room temperature, then cooled to +5 C. and treated with 2.95 cc. of a solution of 13.3 grams of chromium trioxide in 11.5 cc. of concentrated sulfuric acid, made up with water to 50.0 cc. After one hour a solution of 28 grams of crystalline sodium acetate in 50 cc. of water is added, and the whole is diluted with benzene and washed with water. The benzene solution is dried, filtered and evaporated in a water-jet vacuum. The crude product is crystallized from ether and yields 595 mg. of the 18:20-lactone of 3,8:1lu-diacetoxy-20B-hydroxy- 5u-pregnane-18-acid melting at 216-218" C. Optical rotation [u] =23 (in chloroform). Infra-red bands, inter alia, at 5.6911. -lactone); 5.77 (acetates); 8.09, 8.75, 9.74 and 10.44

The mother liquor is evaporated to dryness and the residue is chromatographed on 80 grams of alumina. 600 cc. of a 4:1-mixture of hexane and benzene elute oily compounds (predominantly cyclohexanol acetate). From the fractions eluted with 600 cc. of hexane-[- benzene 1:1 there are obtained by crystallization from ether 89 mg. of 31311lot-(llflCBtOXY-l7-lOdO-5OL-3Ildl05t3fl8 melting at 212-214 C. Optical rotation [a] =+l9 (in chloroform). The following 200 cc. of benzene elute only oily compounds, whereas the second benzene fraction (200 cc.) yields on crystallization from ether 74 mg. of 313:l1a-diacetoxy-l8:20p-oxido-5a-pregnane melting at 140-142 C. The following fraction (200 cc. of benzene) contains a mixture of this compound with the following lactone; a further 400 cc. of benzene and 400 cc. of a 19:1-mixture of benzene and ethyl acetate yield another 276 mg. of the l8:20-lactone of 35:11adiacetoxy-ZOfi-hydroxy-Sa-pregnane-l8-acid melting at 216-218" C.

Example 27 A suspension of 2.5 grams of 3flzl1u-diacetoxy-20flhydrQXy-Su-pregnane and 5.0 grams of crystalline silver acetate in 200 cc. of cyclohexane is treated with 3.5 grams of iodine and then boiled and stirred for 3 hours while being irradiated with a 500- watt lamp, whereupon the color of iodine disappers almost completely and a yellow precipitate of silver iodide forms. The mixture is then cooled, the insoluble salts are filtered on and Washed with cyclohexane. The filtrate is decolorized by being washed with sodium thiosulfate solution, dried and evaporated in a Water-jet vacuum. The crude product (3.345 grams), which contains the 3flzllu-diacetoxy- 18-iodo-20p-hydroxy-5u-pregnane, is dissolved in 100 cc. of acetone, treated with 3.35 grams of potassium acetate and 3.3 cc. of glacial acetic acid and stirred under reflux for 8 hours, then evaporated in a water-jet vacuum. The residue is taken up in methylene chloride and water, the organic layer is again washed with water, dried and evaporated. The residue (3.226 grams) is chromatographed 'on 80 grams of alumina. 800 cc. ofa 4:1- mixtureof benzene and hexane elute oily products. The fractions obtained with 400 cc. of a lzl-mixture of benzene and hexane yield on crystallization from ether a small amount of 3,8:l1u-diacetoxy-17-iodo-androstane melting at 212-2l4 C. The following two fractions eluted with 200 cc. of benzene-l-hexane 1:1 and with 200 cc. of benzene, contain oily by-products. The following fractions (397 mg.) eluted with 600 cc. of benzene yield on crystallization from pentane Bfiilla-diacetoxy-18:20B-oxido-5a-pregnane melting at 140-142 C. Finally, from the fractions (558 mg.) eluted with benzene+ethyl acetate 19:1 and 9:1, unreacted 35:11adiacetoxy-20,8-hydroxy-5a-pregnane used as starting material can be recovered.

Example 28 A mixture of 2.5 grams of 3B:11ot-diacetoxy-20fi-hydroXy-5a-pregnane, silver acetate and iodine is heated as described in Example 27. The resulting crude product (3.46 grams) is dissolved in 50 cc. of acetone, treated with 1.25 grams of silver chromate and then stirred for 30minutes at room temperature, cooled to 0 C., and 2.95 cc. of a solution of 13.3 grams of chromium trioxide in 11.5 cc. of concentrated sulfuric acid, made up with water to 50 cc. After one hour 28 grams of crystalline sodium acetate in 50 cc. of water are added and the reaction mixture is worked up as de- 22 scribed in Example 26. The crude product (3.173 grams) yields on crystallization from ether-l-pentane 478 mg. of crystals (melting at 124126 C. with decomposition) containing about 50% of 3,8:11a-diacetoxy- 18-iodo-20-oxo-5oz-pregnane and about 50% of 35:11adiacetoxy-20-oxo-5a-pregnane. The mother liquor is evaporated to dryness, the residue is dissolved in 100 cc. of acetone, mixed with 3.35 grams of potassium acetate and 3.3 cc. of glacial acetic acid, and the whole is refluxed and stirred for 8 hours at a bath temperature of C., then cooled, evaporated in a water-jet vacuum almost to dryness, and the residue is taken up in methylene chloride and water. The extract is washed with water, dried and evaporated, to yield 2.970 grams of a crude product which on crystallization from ether yields 235 mg. of 3/3:1lu-diacetoxy-ZO-oxo-Sa-pregnane melting at 172-l74 C. The mother liquor is evaporated and the residue is chromatographed on 80 grams of alumina. Elution with 600 cc. of benzene-l-hexane 4:1 and with 600 cc. of benzene+hexane 1:1 furnishes only oily products. From the benzene fraction (800 cc.) another 555 mg. of 35:11ot-diacetoxy-20-oxo-5a-pregnane can be obtained. Elution with the following 400 cc. of benzene+ethyl acetate 14:1 furnishes a total of 385 mg. of a substance from which by crystallization from ether the 18:20-lactone of 3/3:11a-diacetoxy-20B-hydroxy-5apregnane-lS-acid, melting at 216-218 C., can be isolated.

Example 29 A stirred suspension of 5.0 grams of dry calcium carbonate and 15.0 grams of previously dried lead tetraacetate in 500 cc. of cyclohexane is refluxed for one hour, then treated with 1.5 grams of iodine and 5.0 grams of 3 8:1 1u-diacetoxy-ZOfl-hydroxy-Sa-pregnane and further boiled with stirring until the reaction mixture loses its color (18 to 30 minutes). The reaction mixture is cooled to room temperature, filtered through Celite, the residue is rinsed with cyclohexane and the combined filtrates are washed with a solution of 25 grams of sodium thio: sulfate in 100 cc. of water and then three times with Water and finally dried and evaporated. The resulting 6.55 grams of crude 3,8:11wdiacetoxy-20-hydroxy-18- iodo-Swpregnane are dissolved in 100 cc. of acetone and treated while being stirred at 0 C. With 5.9 cc. of a solution of chromium trioxide in sulfuric acid [13.26 grams of chromium trioxide dissolved in 20 cc. of water, diluted with 11.5 cc. of concentrated sulfuric acid and made up with water to 50 00.]. After 30 minutes at 0 C. a solution of 56 grams of crystalline sodium acetate in 100 cc. of water is added and the reaction mixture is extracted with benzene. The organic layer is washed three times with semisaturated sodium chloride solution, dried and evaporated in vacuo, and yields 5.85 grams of an oily product which, after having been redissolved from ether+petroleum ether, yields 4.117 grams of crude 3B:1lot-diacetoxy-l8-iodo-20-oxo-5a-pregnane melting at 118 to 121 C. with decomposition.

Example 30 A solution of 4.20 grams of 3(3:l1m-diacetoxy-18-iodo- 20-oxo-5a-pregnane (amorphous crude product from 3.30 grams of 3B:11ot-diacetoxy-20fi-hydroxy-5a-pregnane) in 400 cc. of methanol is treated with 4.0 grams of silver acetate and refluxed for 3 hours. The precipitated silver iodide (dry Weight 1.210 grams) is filtered off together with the excess silver acetate, the filtrate'is evaporated in vacuo, the residue is taken up in ether, again filtered and the solution is evaporated in vacuo. The resulting product is dissolved as it is in 80 cc. of glacial acetic acid, mixed with 16 cc. of water and heated for 2 hours at .C. The reaction mixture is concentrated in vacuo to about 10 cc., and the residue is diluted with water and extracted with ether. The solution is washed until neutral and dried, to yield 3.30 grams of an amorphous crude product which is dissolved in benzene and chromatographed on neutral alumina (activity II).

lzl-mixtures of benzene and ethyl acetate elute 1.02 grams of 3o:llot-diacetoxy-18-hydroxy-20-oxo-S a-pregnane which is present in the form of an 18:20-semiketal and, after having been recrystallized twice from a mixture of methylene chloride, ether and petroleum ether, melts at 160 to 161 C. Optical rotation 11) 18.21- 1 (0.: 1.098 in chloroform) The infra-red spectrum of the compound contains absorption bands inter alia at 2.82, 5.82, 8.10, 9.73, 10.41 and 11.23;.

Example 31 A suspension of 500 mg. of calcium carbonate and 1.50 grams of lead tetraacetate in 75 cc. of cyclohexane is boiled for one hour while being stirred and then treated with 180 mg. of iodine and 500 mg. of A -3- ethylene-dioxy-ZOB-hydroxy-pregnene. After a further 3.0 minutes at 80 C. the reaction mixture is cooled to room temperature, filtered through Celite, the residue is rinsed with 120 cc. of cyclohexane, and the filtrate is washed as described in Example 29 with sodium thiosulfate solution and then with Water and evaporated in vacuo. The resulting 610 mg. of crude A -3-ethylenedioxy- 18-iodo-20/3-hydroxy-pregnene are oxidized as described in Example 29 with chromium trioxide in sulfuric acid, to yield A 3 ethylene-dioxy-18-iodo-20-oxo-pregnene which is dissolved as it is in 60 cc. of methanol and refluxed for 4 hours with 600 mg. of silver acetate. 198 mg. of silver iodide are filtered 0E and the methanolic solution is then evaporated in vacuo, the residue is taken up in ether and filtered, and the filtrate is once more evaporated in vacuo. (450 mg.) is dissolved in cc. of glacial acetic acid, mixed with 2 cc. of water and heated for one hour at 80 to 90 C. Another 3 cc. of water are added and the reaction mixture is concentrated in vacuo to about 3 cc., once more diluted with water and then extracted with ether. The solution is Washed successively with water, sodium bicarbonate solution and water, dried with sodium sulfate and evaporated in vacuo, to yield 365 mg. of a yellowish foam which, after chromatographic purification on neutral alumina, yields 82 mg. of crystalline 18-hydroxy-progesterone which melts at 154 to 156 C. after having been recrystallized twice from methylene chloride+ether. The infra-red spectrum of this product is identical with that of the authentic 18-hydroxyprogesterone.

Example 32 In a similar manner as described in Examples 29, 30 and 31 the A -3B-acetoxy-ZO-hydroxy-pregnene (5.0 grams) prepared from A -3fi-acetoxy-ZO-oxo-pregnene by reduction with lithium tri-tertiary butoxy aluminum hydride is converted by successive treatment with lead tetraacetate and iodine, chromium trioxide in sulfuric acid, silver acetate in methanol and dilute acetic acid, into the 18:20-cyc1osemiketal of A -3p-acetoxy-18-hydroxy-20-oxo-pregnene which melts at 158 to 161 after having been recrystallized three times from ether-i-hexane. The infra-red spectrum of the compound contains absorption bands inter alia at 2.80, 5.81, 8.10, 9.00, 9.66 and 11.25;.

Example 33 780 mg. of iodine and 2.5 grams of A -3-ethy1enedioxy- 11u-acetoxy-ZOB-hydroxy-pregnene are added to a suspension, previously boiled for 45 minutes, of 2.5 grams of calcium carbonate and 8.0 grams of lead tetraacetate dried in a high vacuum in 250 cc. of cyclohexane, and the mixture is stirred at 80 .C. until it loses its color. The mixture is then cooled to 20 C., filtered through Celite and the filtrate is washed as described in Example 29 with sodium thiosulfate solution and with water and The crystalline crude product evaporated. The resulting A 3 CthYIGHG-dlOXY-llotacetoxy-18-iodo-20-hydroxy-pregnene melts at 153 C. with decomposition after having been recrystallized twice from isopropanol.

What is claimed is:

1. A member selected from the group consisting of a compound having the formula in which R represents a member selected from the group consisting of (1) oxo, (2) lower alkylenedioxy and (3) hydrogen together with acyloxy, R represents a member selected from the group consisting of (1) two hydrogen atoms, (2) oxo and (3) hydrogen together with acyloxy, and R represents a member selected from the group consisting of hydrogen and hydroxy, the 4-dehydro derivatives of the 3-oxo compounds and the S-dehydro derivatives of the 3-lower alkylenedioxy and 3-acyloxy compounds, said acyloxy radicals being derived from a member selected from the group consisting of a carboxylic acid having 1 to 8 carbon atoms, methane sulfonic, benzene sulfonic and paratoluene sulfonic acid.

2. A member selected from the group consisting of a compound having the formula in which R represents a member selected from the group consisting of (1) 0x0, (2) lower alkylenedioxy and (3) hydrogen together with acyloxy, R represents a member selected from the group consisting of (1) two hydrogen atoms, (2) oxo and (3) hydrogen together with acyloxy, and R represents a member selected from the group consisting of (1) 0x0 and (2) hydrogen together with hydroxy, the 4-dehydro derivatives of the 3-oxo compounds and the S-dehydro derivatives of the 3-lower alkylenedioxy and 3-acy1oxy compounds, said acyloxy radicals being derived from a member selected from the group consisting of a carboxylic acid having 1 to 8 carbon atoms, methane sulfonic, benzene sulfonic and paratoluene sulfonic acid.

3. A compound of the formula OH; H: 0-1 5 R in which R represents a member selected from the group consisting of =0, and

4. An unsaturated compound of the formula C Ego-I Egg wherein R represents a member selected from the group consisting of and R represents a member selected from the group consisting of and O -acyl the acyl substituent being derived from an acid selected from the group consisting of a lower aliphatic carboxylic acid, monocyclic cycloaliphatic carboxylic acid, monocyclic aromatic carboxylic acid, monocyclic aryl lower aliphatic carboxylic acid, lower aliphatic sulfonic acid and monocyclic aromatic sulfonic acid. 5. A compound of the formula wherein each of R and R stands for an acyl radical and R for a member selected from the group consisting of wherein R represents an acyl radical and R a member selected from the group consisting of the acyl substituent being derived from an acid selected from the group consisting of a lower aliphatic carboxylic acid, monocycle cycloaliphatic carboxylic acid, monocyclic aromatic carboxylic acid, monocyclic aryl lower aliphatic carboxylic acid, lower aliphatic sulfonic acid and monocyclic aromatic sulfonic acid.

7. A process for the manufacture of a member selected from the group consisting of a saturated and an unsaturated 18-iodo-20 hydroxy-pregnane, an 18-iodo-18,20-oxido pregnane, and an 18-hydroxy-18,20-oxido pregnane, wherein a monohydroxy steriod selected from the group consisting of a saturated and an unsaturated 18-unsubstituted ZO-hydroxy-pregnane compound is treated with a member selected from the group consisting of an N-iodocarboxylic acid amide, N-iodo-carboxylic acid imide, alkyl hypoiodite, acyl hypoiodite, cyanogen iodide, iodine chloride and iodine bromide.

8. Processas claimed in claim 7, wherein the treatment with the iodine containing reactant is discontinued while unchanged starting material can still be detected in the reaction mixture, and the 18-iodo-20-hydroxy compound is isolated.

9. Process for the manufacture of l8-iodo-20-oxosteroid of the pregnane series, wherein a member selected from the group of a saturated and an unsaturated 18-iodo- ZO-hydroxy-compound is oxidized to the corresponding 20-oxo compound by means of a compound of hexavalent chromium.

10. Process for the manufacture of an 18-hydroxy-20- oxO-pregnane compound, wherein a member selected from the group consisting of a saturated and an unsaturated 18-iodo-20-oxo-pregnane compound is treated with a hydrolytic alkaline agent.

11. Process for the manufacture of an 18,20-oxido compound of the pregnane series, wherein a monohydroxy steroid selected from the group consisting of a saturated and an unsaturated 18-iodo-20-hydroXy-pregnane compound is treated with a hydrolytic alkaline agent.

12. Process as claimed in claim 7, wherein there is used as substance forming an acyl hypoiodite, an acylate of tetravalent lead in the presence of iodine.

13. Process as claimed in claim 12, wherein there is used as the acylate of tetravalent lead lead tetraacetate in the presence of iodine.

14. Process as claimed in claim 7, wherein the reaction is performed with the addition of a weak base while irradiating the mixture with ultraviolet light.

15. Process according to claim 7, wherein there is used as the substance forming an acyl hypoiodite mercury acetate in the presence of iodine.

16. Process according to claim 7, wherein there is used as the substance forming an acyl hypoiodite silver acetate in the presence of iodine.

17. Process as claimed in claim 7, wherein the reaction is performed in a saturated cyclic hydrocarbon.

18. Process according to claim 7, wherein the reaction is performed in boiling cyclohexane.

References Cited in the file of this patent UNITED STATES PATENTS 3,087,926 Pappo Apr. 30, 1963 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND HAVING THE FORMULA 